Refine
Has Fulltext
- yes (7)
Is part of the Bibliography
- no (7)
Keywords
- Biochemistry (1)
- HMGB1 (1)
- NXF1 (1)
- RNA Biology (1)
- SR protein (1)
- SRSF3 (1)
- SRSF7 (1)
- VEGF (1)
- alternative 3′ end processing (1)
- bevacizumab (1)
Institute
Die seit dem Ende des 19. Jahrhunderts verstärkt aus der Diaspora nach Palästina übersiedelnden Juden liessen sich bis 1948, dem Jahr der Proklamation des Staates Israel, hauptsächlich in der Küstenzone nieder, was dieser Region zu einem massiven Bevölkerungsübergewicht innerhalb Israels verhalf. Als nach der Staatsgründung die jüdische Bevölkerung vor allem durch die grosse Einwanderungsrate erheblich zunahm, sahen sich die israelischen Planerv eranlasst, einen Teil dieser Bevölkerungsströme planmässig in die dünnbesiedelten Räume des Landes zu lenken. Die dazu notwendigen neuen Siedlungen sollten sowohl als Ausgangspunkte einer industriellen Entwicklung dienen wie auch vielfältige strategische Ziele erfüllen. Nicht zuletzt aber sollten sie den ankommenden Einwanderern einen Raum zur Integration in die israelische Gesellschaft bieten. Als Beispiele zweier israelischer Entwicklungsstädte im ariden Süddistrikt dokumentieren Dimona und Arad eindrücklich die Entwicklung, die die israelische Stadtplanung im Laufe der vergangenen 50 Jahre durchgemacht hat. Das in der Phase einer drückenden Einwanderungswelle als Textilindustriestandort realisierte Dimona wurde noch auf der Planungsgrundlage der weitläufigen Gartenstadt verwirklicht, obwohl man in Europa bereits früher erkannt hatte, dass dieses Modell mit allerlei Mängel behaftet war. Besonders das für eine Umsetzung des Gartenstadtkonzeptes sehr ungünstige Wüstenklima eines Grossteils Israels führte zwangsläufig zu einer Revision der Planungskonzepte israelischer Neustädte. Zu den vielfältigen Problemen in der Anlage Dimonas, die sich insbesondere in der monotonen Bauweise und den verödeten weiten Grünflächen manifestieren, gesellten sich alsbald auch wirtschaftliche und soziale Schwierigkeiten. Aus dem auffallenden Mangel an interessanten und gut bezahlten Arbeitsstellen sowie dem schlechten Image Dimonas als "Einwandererstadt" resultierten zu einem grossen Teil die Probleme der Arbeitslosigkeit und der stagnierenden Bevölkerungszahlen. Trotz der beträchtlichen Bemühungen seitens der verantwortlichen Behörden und Institutionen, die Lebensqualität Dimonas spürbar zu heben und damit die Stadt für potentielle Zuzüger attraktiv werden zu lassen, wartet immer noch eine Menge an langwieriger und schwieriger Arbeit auf die Verantwortlichen der Stadt, die aber noch auf reichlich vorhandene und vielfach ungenutzte Entwicklungspotentiale der Stadt zurückgreifen können. Die bereits von Beginn weg mit vielen Vorschusslorbeeren bedachte Modellstadt Arad weist gegenüber Dimona eine vollständig andersartige Stadtbaugeschichte auf. An die Stelle des Gartenstadtmodells trat in Arad ein Konzept, bei dem eine dichte und klimagerechte Bebauung oberste Leitlinie der Stadtplanung wurde. Notabene geschah diese Umbesinnung in einer Zeit abnehmender Einwanderungszahlen. All die planerischen Bestrebungen hatten einerseits ein hohes Mass an Lebensqualität zum Ziel, andererseits sollte in Arad die bislang gescheiterte Integration der Neueinwanderer erreicht werden. Zu erwähnen sind in diesem Zusammenhang die strengen Auswahlkriterien der ersten Bewohner von Arad, denen eine besondere Aufgabe im Aufbau der Stadt zukam. Nebst der gelungenen Anlage Arads, die besonders auf den umfangreichen planerischen und architektonischen Massnahmen, die ergriffen wurden, basiert, erweist sich auch der vorhandene, breit gefächerte, industrielle Sektor als günstige Basis für die florierende Stadt. Das Modell Arads entpuppte sich als derart erfolgreich, dass es für Länder mit einem hohen Wüstenanteil von grosser Bedeutung ist. Gleichwohl dürfen Arads Probleme, obwohl sie im Vergleich mit anderen israelischen Entwicklungsstädten geringfügig erscheinen, nicht vernachlässigt werden. Besonders die überdurchschnittliche Arbeitslosenzahl und gewisse Mängel in der Tourismusbranche lassen auch in Arad noch Raum für zukünftige Innovationen übrig.
Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends.
Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.
SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.